Pharmaceutical compositions containing substituted 5-nitrofurfurylideneamino-oxazolidinones

ABSTRACT

Compounds of the class of 5-substituted carbamoyloxymethyl-3-(5nitrofurfurylideneamino)-2-oxalidinones have antimicrobial properties; compositions containing such compounds and methods for the treatment of microbial infections and protecting organic material against microbial attack are provided; a typical embodiment is 5-methylcarbamoyloxymethyl-3-(5nitrofurfurylideneamino)-2-oxazolidinone.

United States Patent [191 Hoyle et a].

[ PHARMACEUTICAL COMPOSITIONS CONTAINING SUBSTITUTED S-NITROFURFURYLIDENEAMINO- OXAZOLIDINONES [75] Inventors: William Hoyle, Bramhull; Michael Philip Savage, Heuld Green, both of England [73] Assignec: Ciba-Geigy Corporation Ardslcy.

[22] Filed: June 15, 1972 [21] Appl. N0.: 263,046

Related US. Application Data [62] Division of Ser. No. 43,586, June 4, I970, Pat. No.

[51] Int. Cl. A61K 31/42 51 Sept. 16, 1975 [58] Field of Search 424/272 [56] References Cited UNITED STATES PATENTS 3,470,164 9/[969 Takzlmatsu 424/272 3534,4[2 H1972 Breucr t. 424/272 Primary Examiner-V. D. Turner Attorney. Agent, or Firm-Joseph G Kolodny; John J. Mzlitner; Theodore O. Groeger [57] ABSTRACT Compounds of the class of 5-substitutcd earbamoyloxymcthyl-3-(5-nitrofurfurylideneamino)-2 oxz1lidinones have antimicrobial properties; compositions containing such compounds and methods for the treatment of microbial infections and protecting organic material against microhizil attack are provided; a typical embodiment is 5-methyleurhamoyloxymethyl-3-(5- nitrofurfurylideneumino)-2-oxazolidinone.

3 Claims. No Drawings PHARMACEUTICAL COMPOSITIONS CONTAINING SUBSTITUTED 5-NITROFURFURYLIDENEAMINO- OXAZOLIDINONES This is a division, of application Ser. No. 43,586, filed June 4, 1970 now US. Pat. No. 3,686,170.

DETAILED DESCRIPTION The present invenion relates to substituted 5- nitrofurfurylideneamino-oxazolidinones with antimierobial properties, to pharmaceutical and feedstuff compositions, as well as to methods for the treatment of microbial infections in mammals and to methods of protecting organic material against microbial attack.

More particularly, the present invention pertains to compounds of the formula I,

wherein R is hydrogen or a group COR wherein R is hydrogen, alkyl having at most six carbon atoms or alkenyl having from two to six carbon atoms, and R is hydrogen, alkyl having at most three carbon atoms or alkenyl having three or four carbon atoms, whereby at least one of the symbols R, and R is different from hydrogen.

R as an alkyl group may be methyl, ethyl, n-propyl or isopropyl. R;, as an alkyl group may be e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiarybutyl, n-pcntyl or nhexyl.

R as an alkenyl group may be allyl, Z-methallyl, but- Z-enyl (crotyl) or but-3-enyl. R; as an alkenyl group may be e.g. vinyl, allyl, 2-metally1, but-Z-enyl (crotyl), but-3-enyl, pentl-enyl, pcnt-Z-enyl, hex-l-enyl or hexadienyl', straight or branched-chain alkenyl groups containing three or four carbon atoms are, however. particularly preferred.

The compounds of the present invention are prepared by reacting 5-nitro-2-furfurylideneaminohydroxymethyl-oxazolidinone having the formula II,

with an isocyanante R NCO or an alkanoyl-isocyanate R;,CO.NCO, wherein R and R are as previously defined. Compounds of formula II are described and claimed in British Pat. No. 735,136.

The process may be carried out under a wide variety of reaction conditions, preferably at an elevated temperature within the range of from 75C to the boiling point under reflux of the reaction mixture. Preferably, the reaction is carried out in the presence of an organic medium which is essentially inert under the reaction conditions, for example, dioxan at 100C. A tertiary organic base is preferably present in the reaction mixture, for instance diazo-bicyclo-octane, in a catalytically active proportion.

If an isocyanate R .NCO is used, the product is a compound having the formula lllA,

If an alkanoyl isoeyanate R, CO NCO is used in the process, the product is a compound having the formula IIIB,

The present invention also provides a second process of producing a compound of formula I, which comprises reacting a 5-nitrofurfurylideneamino-Z- oxazolidinone having the formula lllA with an acylating compound containing the structure CO.R wherein R is as previously defined.

The acylating compound used in the second process of the invention may be, for example, a carboxylic acid, carboxylic acid anhydride or mixed anhydridc. or acid chloride. The process may be carried out by heating the reactants together. if desired in the presence of an acidic or basic condensing agent or dehydrating agent. Examples of condensing agents which may be used, inelude sulphuric acid and other acids, and trimethylamine, triethylamine, pyridine, dimethylanilinc and other tertiary organic bases.

The present invention also provides a third process of producing a compound of formula I, which comprises reacting 5-nitro-2-furaldehyde or a compound capable of producing 5-nitro-Z-furaldehyde under the reaction conditions with a substituted oxazolidinone having the formula IV,

wherein R and R are as previously defined, and ZN is the HO.CH NH group or an NH.CO- lower alkyl group or Z is the divalent grouping:

wherein each of the groups R and R is an alkyl group having from one to five carbon atoms, or wherein R is hydrogen and R is a straightor branched-chain alkyl group containing from one to five carbon atoms or an aryl group unsubstituted or hearing nitro-. alkylor halogensubstituents.

If either or both of the groups R, and R in the grouping Z is alkyl. the alkyl radical is preferably methyl. ethyl. n-propyl or isopropyl.

If the group is R; is aryl, the aryl group is preferably a phenyl radical. If the group R,-, is an alkyl-substituted aryl group. it is preferably a tolyl or another methyl substituted phenyl radical. If the group R is halogensubstituted aryl, the halogen-substituted aryl group is preferably a monochloro-substituted phenylor monochloro-substituted alkylated phenyl radical. [f the group R; is a nitro-substituted aryl. the nitrosubstituted aryl group is preferably a mononitrosubstituted phenyl radical.

Preferably. the grouping Z is an aralkylidene or an alkyl-. halogenor nitro-substituted aralkylidene group. Examples of divalent grouping Z. which may be present in the oxazolidinone reactant of formula IV. include isopropylidene. bcnzylidene. p-methylbenzylidene. pchlorobenzylidene and p-nitrobenzylidene groupings.

Instead of using 5-nitro-2furaldehyde as reaxtant in the third process of the invention. a compound capable of producing S-nitro-Z-furaldehyde under the reaction conditions may be employed as a source of the 5-nitro- Z-furaldehyde. for example. the diacetate of another functional derivative of 5-nitro-Z-furaldehyde.

The third process of the invention may be conveniently carried out by heating the reactants together in an organic solvent. Preferably, the solvent used is substantially inert under the conditions of the reaction. and may be for example. methanol. ethanol, isopropanol. nbutanol or other lower alkanol or a mixture of two or more thereof. or benzene. toluene or other aromatic hydrocarbon solvent or a mixture of two or more thereof. The reaction may be promoted. if desired. by having aqueous hydrochloric and/or other mineral acid. or glacial acetic acid present in the reaction mixture.

The present invention also provides a fourth process of producing a S-nitro-Z- furfurylideneaminooxalolidinone of formula I. which comprises nitrating a compound having the formula V.

wherein R and R are as previously defined.

The nitration may be carried out with nitric acid under conditions conventional in nitrating substituted furyl derivatives. for instance by reacting in the pres ence of a water-binding agent; the water-binding agent may be. for example. sulphuric acid. but is preferably acetic anhydride. lfdcsired. a proportion of acetic acid may be present in the reaction mixture. The nitration is preferably carried out at a temperature not exceeding l5C using concentrated or fuming nitric acid. The reaction may be carried out. for instance. by adding in portions the oxazolidinone of formula to a mixture of concentrated or fuming nitric acid. acetic acid and acetic anhydride while maintaining the temperature at from 5 to 15C. preferably about 10C. If desired. the

compound of formula V may be produced during the nitration by reacting the compound having the formula VI.

COO (Vl) together with an acylating agent containing the group -CO.R The acylating agent may be, for example, a carboxylic acid anhydride or mixed anhydride, or an acid chloride, but is preferably acetic anhydride or other carboxylic acid anhydride.

The compounds of the present invention having the formula I. have valuable anti-microbial properties. and in particular have anti-bacterial, anthelminthic, coecidiostatic. trypanocidal and anti-malarial activity of value in human or veterinary medicine. The compounds are particularly valuable in the treatment of infections of the intestinal and urinary tracts. The compounds may also be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial deterioration by contacting the organic material with. impregnating in, or otherwise treating with. the compounds. The compounds also find application as growth-promoting additives to animal feedstuffs.

The anti-microbial properties of the compounds of the invention are demonstrated in a variety of standard in vitro and in vivo tests. Thus. 5- methylcarbamoyloxymethyl-3-( S-nitrofurfurylideneamino )2-oxazolidinone. 5 cthylcarbamoyloxymethyl-3-( 5-nitrofurfurylideneamino )Z-oxazolidinone and 5- allylcarbamoyloxymethyl-3-( S-nitrofurfurylideneamino)-2-oxazolidinone have been found to have an excellent activity against Staphylococcus. ILiStlILl'iC/lftl coll. Klebsiella. Salmonella and other bacteria.

The toxity of the compounds of the invention as determined in mice on oral administration is of favoura bly loyv order.

For their internal use in mammals. the compounds of formula I are administered orally in daily dosages of from about 1 to about 50 mg/kg. although the exact dosage has to be adjusted to the type of infection. the age. weight and the particular condition of the host being treated.

The compounds ofthe present invention are administered advantageously in form of a pharmaceutical composition comprising an anti-microbially effective amount of a compound of formula I and a pharmaceutically acceptable carrier therefor.

The pharmaceutical compositions according to the invention contain at least one compound of formula I as active substance together with a conventional phar maceutical carrier. The type of carrier actually used depends to a great extent on the intended application. For external application. for example in disinfecting healthy skin. disinfecting wounds and in treating dermatoses and infections of the mucous membranes caused by bacteria. ointments. powders and tinctures are particularly useful. The ointment bases may be anhydrous. for instance they can consist of mixtures of wool fat and soft paraffin, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are for instance, rice starch and other starches; the bulk weight of the carriers may be made lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum. The tinctures may contain at least one active ingredient of the formula I in aqueous ethanol, in particular 45% to 75% ethanol, to which to of glycerol may be added, if desired. Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin. The content of active ingredient in pharmaceutical compositions for external application is preferably in the range of from 0.1% to 5%.

Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth, are suitable for the disinfection of the mouth and throat. The former are preferably prepared from alcoholic solutions containing 1% to 5% of active substance to which glyc erol or flavourings may be added. Lozenges, that is solid dosage units, preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2% to 20% by weight, as well as the usual conventional additives, such as binding agents and flavourings.

Solid dosage units, in particular tablets, dragees (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the oral treatment of urinary tract infections. These units preferably contain from 10% to 90% of the compound of the formula I, to enable the administration of daily dosages of from 0.1 to 2.5 grams to adults, or of suitably reduced doses to children. Tablets and dragee cores are produced by combining the compounds of formula I with solid, puverulent carriers such as lactose, saccharose, sorbitol. maize starch, potato starch or amylopectin, cellulose derivatives or gelatines, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Dragee cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/or titanium dioxide, or they may be cooated with a lacquer dissolved in volatile organic solvents or a mixture of solventsv Dyestuffs can be added to these coatings, for instance to differentiate between varying dosages. Soft gelatine capsules consist, for example, of a mixture of gelatines and glycerol and may contain, for example, mixtures of the compound of formula I with polyethylene glycol. Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatines, and magnesium stearate or stearic acid.

In all forms of administration, compounds of the formula I can be present as sole active ingredients or they can also be combined with other known pharmacologieally active, and especially anti-bacterial and/or antimycotically or other anti-microbially active substances, for example to broaden the range of applications. They can be combined, for example, with 5,7-dichloro-2- methyl-S-quinolinol or other derivatives of 8- quinolinol, with sulfamerazine or sulfafurazole or other derivatives of sulfanilamide, with chloramphenicol or tetracycline or other anti-biotics. with 3.4-,5- tribromosalicylanilide or other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones. or with polychlorohydroxy-diphenylmethanes, with halogen-dihydroxydiphenyl sulphides, with 4,4-dichloro-2-hydroxydiphenylether or 2,4,4'-trichloro-2-hydroxydiphenylether or other polyhalogenhydroxydiphenylethers, or with bactericidal quaternary compounds or with certain dithiocarbarnic acid derivatives such as tetramcthylthiuram disulphide. Also, carriers which themselves have favourable pharmacological properties may be used, for instance sulphur, as a powder base or zinc stearate as a component of ointment bases.

The invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attack which comprises treating the material with a compound of formula 1. The organic material may be, for instance, a natural or synthetic polymeric material, a proteinaceous or carbohydrate substance. or a natural or synthetic fibre or textile material formed therefrom.

The invention also provides an animal feedstuff composition comprising a 5-nitro-2- furfurylideneaminooxazolidinone of formula I in an amount sufficient to promote the growth of the animal fed with the composition.

The following examples will serve to further typify the nature of the present invention. but they. in no way. should be construed as a limitation on the scope thereof. The temperatures are given in degree Centigrades.

EXAMPLE 1 A suspension of 25.5 g of 5-hydroxymcthyl-3-(5- nitrofurfurylideneamino)-2-oxazolidinone, 10 ml of methyl isocyanate and 0.75 g of diazabicyclo-octanc in 300 ml of dioxan is stirred at C for 8 hours. The resulting clear solution is poured into 200 ml of water and the crystalline productis filtered. recrystallised from aqueous dimethyl formamide and dried.

The product is 5-methylcarbamoyloxymethyl-B-( 5- nitrofurfurylideneamino)-2-oxazolidinone. having melting point 179C.

EXAMPLE 2 The procedure described in Example 1 is carried out using ethyl isocyanate as starting material instead of methyl isocyanate, the reaction conditions being the same.

The product is 5-cthylcarbamoyl vxymcthyl-3-(5- nitrofurfurylideneamino )-2-oxazolidinonc, having melting point 215C.

EXAMPLE 3 The procedure described in Example 1 is carried out using propyl isocyanate as starting material instead of methyl isocyanate. the reaction conditions being the same.

The product is 3-(5-nitrofurfurylideneamino)-5- propylcarbamoyloxymcthyl-2-oxazolidinone, having melting point 189 to 190C.

EXAMPLE 4 The procedure described in Example 1 is carried out using allyl isocyanate as starting material instead of methyl isocyanate. the reaction conditions being the same.

The product is -allylcarbamoyloxymethyl-3-( 5- melting EXAMPLE 7 The procedure described in Example 6 is carried out using crotonic anhydride as starting material instead of acetic anhydride. the reaction conditions being the same.

The product is 5-( N-crotonoyl-N- methylcarbamoyloxymethyl )-3-( S-nitrofurfurylidcneamino)-2-oxalolidinone having point lo8l6)(.

melting EXAMPLE 8 The procedure described in Example 1 is carried out using N-acetyl isocyanate as starting material instead of methyl isocyanatc. the reaction conditions being the same.

The product is 5-N-acetylcarbamoyloxymcthyl-3( 5- nitrot'urfurylideneamino)-Z-oxazolidinone. as confirmed by NMR and IR spectroscopy, and apparently ha ing melting point l53"(v EXAMPLE 9 The procedure described in Example 1 is carried out using 3-l'urfurylidcnc-amino-S-hydroxymethyl-Z oxazolidinone. as starting material instead of 5- hydroxymethyl-3-( 5-nitroturturylidene-amino )-Z- oxazolidinone. the reaction conditions being the same.

The intermediate product thus prepared is 3- furt'urylidenc-amino-5mcthylcarbamoy loxymeth l-Z- oxazolidinonc. having melting point ZOZ-Z03(.

To a mixture of 10.3 g of acetic anhydride and ll) g of concentrated nitric acid is added 2.0 g of 3- furturylideneamino-S-mctl1ylcarb;tmtvyloxymethyl-Z' oxazolidinonc in .portions with cooling. The resulting mixture is allowed to stand and the product filtered and layer chromatography.

To 25 -ml of concentrated sulphuric acid is added an intimately ground mixture of 0.85 g of sodium nitrate and 2.6 g of 3-furfurylidencamino-S- methylcarbamoyloxymethyl-2-oxazolidinone with stirring. After 1 hour the dark red solution is poured onto ice giving an oil containing S-methylcarbamoyloxymethyl-3-( S-nitrofurfurylidene-amino Z-oxazolidinonc as shown by thin layer chromatogra- P y- EXAMPLE l0 The procedure described in Example 1 is carried out using 3-benzylideneamino-S-hydroxymethyl-Z- oxazolidinone as starting material instead of 5- hydroXymethyl-3( 5-nitrofurfurylidcneamino )-2- oxazolidinone, the reaction conditions being the same.

The intermediate product thus prepared is 3 benzylideneamino-Smethylcarbamoyloxymethyl-2- oxazolidinone. having melting point 137l 38C.

A mixture of 0.3 g of 3-benzylidenc-amino-S- methylcarbamoyloxymethyl-l-oxazolidinone and dilute sulphuric acid is steam distilled. The resulting aqueous solution is treated with 0.3 g of S-nitro-Z- fur-aldehyde in 3 ml of ethyl alcohol.

The product is filtered and dried.

The product is 5-methylcarbamoyloxymethyl-3-(5- nitrofurfurylidcneamino )-2-oxa7.olidinone, having melting point 179C and being identical with the product of Example I.

EXAMPLE I l Preparation of 'l'ablets A mixture consisting of g of methylcarbamoyltixymcthyl-3-( S-nitrot urfurylideneaniino)-Z-oxazolidinone. (v0.0 g of maize starch and 35.0 g ot lactose is moistened with a solution of 5.0 g of gelatin and 3.0 g of glycerol in 70.0 g of water and granulated through a sieve. The granulate is mixed with a mixture of 15.0 g of talcum. 10.0 g ot maize starch and 2.0 g ol' magnesium stearate. The resulting mixture is pressed into l.000 tablets. each containing 100 mg of active substance. If desired. the tablets can be grooved for better adaption of the dosage.

EXAMPLE 12 Preparation of Dragdcs ('oinposilion l'or [.000 dragc cs I oxa/olidinonc lllll o g Mai/c starch 27.0 (ielatin so 54 ll (ilxccrol It] g Distilled LllL'l' t .s .id lllt) nil Mai/c starch 10.0 g

lll lalcuni 7.0 g Magnesium stcziratc 1.0 g

l\ \\'hitc dragcc coating vShellac 1.0 g Sugar 50.0 g lalcum 38.0 g itlm arabic v 7.4 g ('olloidal silicon dioxide 2 I g litanitun tl|\ \nlc 0.4 g

Composition 1 is granulated in the heat with composition 11 through a sieve of 1.2 mm mesh diameter. The dried granulate is mixed with composition [11 and the resulting mixture is pressed into 1,000 dragee cores. These are then coated with composition IV and dried. The dragees obtained weigh 255.0 mg and contain 100 mg of active substance.

EXAMPLE 1 3 Preparation of a Syrup Composition: S-Allylearbamoyloxymethyl- 3-( 5-nitrofurfurylideneamino 2 oxazolidinone 100.0 g Colloidal silicon dioxide 13.0 g p-Hydroxyhenzoic acid methyl ester 1.4 g p Hydroxybenzoic acid propyl ester 0.6 g Citric acid 1.0 g Sodium cyclamate 5.0 g Distilled water 610.0 g Glycerol 100.0 g Sodium carboxymethyl cellulose 4.0 g Sugar 320.0 g

The active substance and the colloidal silicon dioxide are passed through a sieve of 1.2 mm diameter (1).

The p-hydroxybenzoic acid esters, the citric and the sodium cyclamate are dissolved in the given amount of boiling distilled water; the glycerol is then added to this solution (11). The sodium carboxymethyl cellulose and the sugar are thoroughly mixed (lll).

Composition 111 is then added at 75C to solution 11 under stirring until complete dissolution of 111. The viscous, slightly turbid liquid is cooled to room temperature. filtered, if necessary, and mixed with composition 1. Water is added to the resulting mixture up to the prescribed weight of 1,155.0 g, and the syrup obtained is homogenized.

What is claimed is:

l. A pharmaceutical composition useful for treating bacteria comprising an antibacterially effective amount of a compound having the formula wherein R is hydrogen or a group CORg wherein R is hydrogen, alkyl having at most six carbon atoms or alkenyl having from two to six carbon atoms, and

R is hydrogen or alkyl having at most three or four carbon atoms, whereby at least one of the symbols R and R is different from hydrogen, and a pharmaceutically acceptable carrier therefor.

2. A method for the treatment of a mammal suffering from a bacterial infection. which method comprises administering to said mammal an anti-bacterially effective amount of a composition according to claim 1.

3. A method of protecting an organic material susceptible to bacterial attack, which comprises applying to the material an antibactcrially effective amount of the composition. 

1. A PHARMACEUTICAL COMPOSITION USEFUL FOR TREATING BACTERIA COMPRISING AN ANTIBACTERIALLY EFFECTIVE AMOUNT OF A COMPOUND HAVING THE FORMULA
 2. A method for the treatment of a mammal suffering from a bacterial infection, which method compRises administering to said mammal an anti-bacterially effective amount of a composition according to claim
 1. 3. A method of protecting an organic material susceptible to bacterial attack, which comprises applying to the material an antibacterially effective amount of the composition. 